The present invention relates to pentafluoroalkane sulfinyl naphthalenes and related compounds, compositions containing those compounds, their use as estrogen receptor modulators, and their use in inhibiting breast and uterine carcinoma. Breast carcinoma or cancer is a major medical problem for women beginning in the third decade of life and continuing throughout senescence. It is currently estimated that in the United States women have a one in eight chance of developing the disease in their lifetime (by the age of eighty), whereas one in twenty-eight women have a lifetime risk of dying from breast cancer (Harris et. al., Ed. Diseases of the Breast, 1996: pp. 159-168). Carcinoma of the breast is the third most common cancer, and the most common cancer in women. It is a major cause of mortality in women, as well as a cause of disability, psychological trauma, and economic loss. Breast carcinoma is the second most common cause of cancer death in women in the United States, and for women between the ages of 15 and 54, the leading cause of cancer-related death (Forbes, Seminars in Oncology, vol. 24(1), Suppl 1, 1997: pp. S1-20-S1-35). Indirect effects of the disease also contribute to the mortality from breast cancer including consequences of advanced disease, such as metastases to the bone or brain. Complications arising from bone marrow suppression, radiation fibrosis and neutropenic sepsis, collateral effects from therapeutic interventions, such as surgery, radiation, chemotherapy, or bone marrow transplantation—also contribute to the morbidity and mortality from this disease.
The epidemiology of this disease, although the subject of intense investigation, is still poorly understood. There appears to be a substantial genetic component which predisposes some women to contract the disease. Yet it is not clear whether this genetic component is causative or permissive to the disease, or only predictive of the disease process. Although it has been known for a long time that breast carcinoma tends to occur more frequently in some families, such analysis is not always predictive of disease occurrence in other family members and is of little value for prediction of its prevalence in the general population. It is currently estimated that only 5% of all breast cancers result from a genetic predisposition (Harris et. al., Ed. Disease of the Breast, 1996: pp. 159-168).
Extensive clinical and pharmacological investigation has been conducted in the attempt to elucidate the relationship between the hormone estrogen, and the cause and maintenance of breast carcinoma. Risk factors for the disease are principally related to the duration of a woman's cumulative estrogen exposure and include: age at menarche, parity, age at the time of the first full-term pregnancy, and menopause. Although much is known about the relationship of estrogen in the maintenance of the disease and the importance of estrogen dependence with respect to endocrine treatment of the disease, there is considerable controversy over the role of estrogen in the pathogenesis of this disease, i.e., whether estrogen is a causative agent (initiator), or an obligatory co-factor (promotor) in the process of carcinogenesis.
Estrogen, which includes 17-beta-estradiol, estrone, and their active metabolites, is a major sex-related hormone in women, but additionally, it appears to be an important homeostatic hormone in both men and women throughout their adult life. All humans have some level of endogenous estrogen. Yet the vast majority of people do not develop breast carcinoma, supporting a position that estrogen, per se, is not an initiator of carcinogenesis, such as is the case with a chemical or environmental carcinogen. Additionally, women, as they go through menopause with the consequent loss of endogenous ovarian estrogen production, do not experience a commensurate reduction in their risk of contracting this disease. In fact, apart from a personal history of breast cancer, age is the single greatest risk factor for developing this disease. Breast cancer is rare in women younger than age 20, but this risk increases rapidly with age. When compared with a 20-year-old woman's risk of developing breast cancer, a woman age 40 to 49 has a 40-fold increase in risk, a woman age 50 to 59 a 60-fold increase, and a woman over the age of 60 has a risk 90-fold higher than that of her younger counterpart (Forbes, Seminars in Oncology, vol. 24(1), Suppl 1, 1997: pp. S1-20-S1-35).
Theories and evidence regarding the role of estrogen in the pathogenesis of this disease are complex. Experimental models of mammary carcinoma in rats require administration of a carcinogen for tumor induction (tumorigenesis), whereas estrogen behaves as a promoter (rather than an initiator) of this process. Ovariectomy, in these animal models, will interfere with this process of chemically-induced carcinogenesis. In humans, however, the timing of the carcinogenic event is unknown. What is known is that women who undergo premature menopause or medical or surgical oophorectomy before the age of 40, will have an approximately 50% reduction in breast cancer risk compared with women undergoing natural menopause at age 50 (Harris, et. al., Ed. Diseases of the Breast, 1996: pp. 159-168). It is logical, therefore, that approaches for the prevention of breast cancer would target the reduction in lifetime estrogen exposure. This can be accomplished by pharmacologically-induced estrogen deprivation, through the administration of an agent which would block the production and/or action of estrogen anywhere along the hypothalamic-pituitary-gonadal axis. It is nevertheless problematic to extrapolate the probable success of preventing breast carcinoma, de novo or otherwise, with agents of this nature.
In contrast to the complex role of estrogen in the pathogenesis of this disease, and despite a continually evolving body of data, considerable advances have been made in our understanding of the effects of estrogen in the setting of established breast carcinoma. Estrogen is a growth factor to most breast carcinoma cells in the early stages of the disease. The rapidly dividing cells are sensitive to its effects through the estrogen receptor. It has also been established, although not well understood that, at some point during the course of this disease process, transformed (cancer) cells often lose their sensitivity to the promoting effects of estrogen. Eventually, a majority of carcinoma cells become independent of estrogen for growth and lose their responsiveness to hormonally based therapy, which broadly includes: the GNRH agonists, tamoxifen, progestins, and androgens.
Enormous benefit in the treatment of breast cancer has been achieved with the advent and widespread use of hormonally based therapeutic interventions. The most extensively used endocrine therapy is tamoxifen. The five-year survival rate for women with breast carcinoma has been dramatically improved with this therapy; however, no additional benefit or survival advantage is achieved by continuing therapy for more than five years. In fact, data indicate a decrease in disease-free survival as well as overall survival, with greater than five years tamoxifen use (NSABP B-14 Trial; Fisher et al. Five Versus More Than Five Years of Tamoxifen Therapy for Breast Cancer Patients With Negative Lymph Nodes and Estrogen Receptor-Positive Tumors, J Natl Canc Inst, vol. 88)(21): pp. 1529-1542, 1996). Unfortunately tamoxifen is also associated with significant adverse effects such as: a significantly increased incidence of venous thromboembolism, substantially increased incidence of vasomotor symptoms or hot flashes (in the range of 16-67%), cataract formation, and DNA-adduct formation which, although not clinically confirmed, still raises concerns about the potential for hepatocellular carcinoma (observed experimentally in animal models). The most serious event, however, is tamoxifen's estrogenic effect in the uterus which causes endometrial hyperplasia and a substantial increase in the incidence-of endometrial carcinomas (a three to four-fold increase in risk after five years tamoxifen-administration) (Goldhirsch et. al., Endocrinie Therapies of Breast Cancer, Sem in One, vol. 23(4), pp. 494-505, 1996). For this reason and the lack of improvement in survival advantage with long-term tamoxifen use, tamoxifen therapy of longer than five years is now contraindicated.
Data suggest that with long-term tamoxifen exposure, breast tumor cells undergo alterations that cause them to develop resistance to its antiestrogenic effects, and alternatively respond to its estrogenic properties (Santen, Editorial: Long Term Tamoxifen Therapy: Can an Antagonist become an Agonist?, J Clin Endo & Metab, vol. 81(6), pp. 2027-2029, 1996). Changes in any step in the estrogen receptor signaling pathway may be responsible for the mechanism of development of resistance to tamoxifen therapy, some of which do not cause cross-resistance to other hormonal therapies and some of which do result in complete unresponsiveness to endocrine therapy of any kind. One mechanism for tamoxifen resistance has been attributed to the gradual evolution of the carcinoma cells from estrogen dependence to estrogen independence (estrogen receptor positive cells become estrogen receptor negative). Thus, even with the most advanced available combinations of treatment modalities, (surgery, radiation, and/or chemotherapy), the long-term prognosis for patients is poor, especially when metastatic disease is present. Clearly, there is a great need for improved therapies and, perhaps most important, a critical need for the prevention of the disease in the first instance (de novo, or primary prevention).